Various methods have been proposed in the past for the sterilization of glucocorticosteroids. PT-A-69652 discloses the cold sterilization of micronized glucocorticosteroids using mixtures of ethylene oxide and carbon dioxide, since, according to PT-A-69652, steroids in powder form are not stable at temperatures above 60° C. Specific examples of glucorticosteroids are prednacindone, dexamethasone and prednisolone, and salts, esters and fluoro derivatives thereof, including dexamethasone acetate, dexamethasone phosphate, prednisolone pivalate and 9-alphafluoro prednisolone. However, ethylene oxide is toxic and when it is used to sterilize glucocorticosteroids it has been found that the residual amounts of the ethylene oxide contravene pharmaceutical guidelines which require very low levels of residual ethylene oxide. Accordingly this method has been found to be unsuitable for producing therapeutically acceptable glucocorticosteroids and formulations thereof.
U.S. Pat. No. 3,962,430 discloses a method for the production of sterile isotonic solutions of medicinal agents, which comprises adding the agent to a saturated solution of sodium chloride in water at 100° C. and then heating the mixture at 100-130° C. This method is not suitable for suspensions of fine particles of glucocorticosteroids which are intended for inhalation because the water, and the heating and cooling involved, produce unfavorable changes in the size of the particles. Indeed it can lead to the formation of bridges between the fine particles producing large, hard aggregates which will not deaggregate into the desired fine particles upon administration.
A putative alternative is dry heat sterilization. According to the European Pharmacopoeia (1996, pp. 283-4) a normal heat sterilization process runs at 180° C. for 30 min or at a minimum of 160° C. for at least 2 hours. According to Pharmacopoeia Nordica (1964, pp. 16) such a sterilization can be carried out at 140° C. for 3 hours. However at the temperatures of these processes glucocorticosteroids suffer significant degradation and are subject to changes in their surface structure.
Sterilization by β- or γ-irradiation is also known. Indeed Illum and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174 recommend the use of such irradiation to sterilize glucocorticosteroids. However when such irradiation is used to sterilize certain finely divided, e.g. micronized, glucocorticosteroids, they are significantly degraded.
WO-A-96/09814 to Andaris Ltd. relates to spray-dried particles of a water-soluble material with a mass median particle size of 1 to 10 μm. The aim of the invention is to produce uniform and reproducible particles for use in dry powder inhalers. The water-soluble material is preferably a human protein or a fragment thereof, in natural or recombinant form, e.g. human serum albumin (HSA), alpha-1 antitrypsin or alcohol dehydrogenase. Also combinations of an active material with a carrier were produced e.g. budesonide and lactose. It is stated generally that the microparticles produced can be sterile without teaching how this could or would be achieved nor showing any proof thereof.
WO-A-96/32095 to Astra AB relates to a process for the preparation of respirable particles by dissolving an inhalation compound in a solvent, introducing the resulting solution containing the inhalation compound in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation. Budesonide with a mass median diameter (MMD) of less than 10 μm is produced with the process. There is no information in WO-A-96/32095 about sterilization or sterile particles.
WO-A-92/11280 to Instytut Farmaceutyczny relates to a method of obtaining (22R) diastereoisomer of budesonide by a condensation reaction followed by crystallizing the crude product of condensation from ethanol. The obtained 21-acetate of budesonide (22R) is hydrolyzed and the product thus obtained is crystallized from ethyl acetate. The content of (22S) diastereoisomer of budesonide is 1% or less. There is no information in WO-A-92/11280 about sterilization or sterile particles.
We have also found that attempts at terminal sterilization of the pharmaceutical formulations, especially suspensions, e.g. aqueous suspensions, of glucocorticosteroids have all proved unsatisfactory. Such suspensions can not normally be sterilized by sterile filtration as most of the particles of glucocorticosteroid will be retained on the filter. We have also shown that moist heat sterilization, e.g. steam treatment of glass vials containing the product, leads to an unacceptable change in particle size.
Various aqueous suspensions of finely divided glucocorticosteroids are known, e.g. the budesonide-containing product known as Pulmicort® nebulising suspension. (Pulmicort® is a trademark of Astra AB of Sweden). Similar formulations of fluticasone propionate are known from WO-A-95/31964.
Accordingly a new process for the sterilization of glucocorticosteroids (and formulations containing them) is required.
Surprisingly we have now found that effective sterilization of dry glucocorticosteroids can be carried out at a significantly lower temperature than that considered necessary for the heat sterilization of other substances. Such sterile glucocorticosteroids can be used in the preparation of sterile formulations containing them.